Synaptic origins of cerebellar disease

Speaker: Roy V. Sillitoe

Department: Jan and Dan Duncan Neuroloigcal Research Institute

Location: Erasmus MC Rotterdam

Date: 06-06-2016

Author: Carolien Bastiaanssen

In neurological movement disorders such as ataxia, dystonia, and tremor the patient suffers from involuntary muscle contractions. Roy Sillitoe and his colleagues aim to answer question such as how do circuits in the brain form and what are the electrophysical consequences when the wiring up does not go according to plan? In order to gain more understanding in how circuits form and function they use the cerebellum as a model system. In this way they also hope to get more insight into disease like dystonia and maybe even develop a treatment.


Figure 1. Location of the cerebellum.

The cerebellum is a part of the brain that is located at the bottom of the brain (Figure 1). This region of the brain is involved in movement, it is responsible for coordination, fine-tuning and motor learning. The cerebellum may also be involved in other cognitive functions like speech but this is still subject of debate. One of the dominant cell types in the cerebellum are the Purkinje cells (Figure 2). These neurons have parallel and climbing fibers through which they receive input. One of the main regions of the brain that provides input to the cerebellum is the so called inferior olive. All these input signals are integrated and the output is send to the deep cerebellar nuclei. Purkinje cells have two types of action potentials: single and complex. In this way the Purkinje cells provide feedback for motor coordination.

purkinje cell

Figure 2. Purkinje cell in the cerebellum.

Researches often make mouse models of diseases. However, most of the mouse models that were based on human genetic studies did not display dystonic symptoms. Now Sillitoe and his colleagues work on a different mouse model and this model does show dystonic symptoms. It is known that cerebellar nuclei function is abnormal in dystonia and that dysfunction of Purkinje cells is linked to this disease. The type of abnormalities implicate that the inferior olive works as a trigger for dystonia. So Sillitoe and his colleagues asked themselves whether the inputs to the motor system could be at fault in dystonia. The inferior olive to cerebellum connection is a good candidate because it’s thought to control timing and/or error correction during movement and learning. This gave rise to the idea of using the inferior olive to cerebellum circuitry as an inroad for designing a more flexible model for understanding dystonia. The goal (or rather wish list) was to generate a genetic mouse model that exhibits dystonia and that is experimentally tractable for development, behavior, anatomy and physiology.

They started with the hypothesis that selectively silencing developing olivo-cerebellar synapses will cause circuit malformations that induce dystonia in mice. They could not just cut the entire olive because that would have severe consequences for the development of the mice. It is however difficult to target the inferior olive because its gene expression pattern overlaps with connected regions. They therefore chose to use a unique intersection of gene expression in the inferior olive (Ptf1a and Vglut2). This caused the inferior olivary neurons to release empty vesicles and thus no response is triggered. The mice indeed showed symptoms of dystonia and the mice were further studied by amongst others electromyography (EMG), measuring local field potential (LFP) and single-unit recordings.

The next step was to test how the mice could be treated. Sillitoe and his colleagues for example used deep brain stimulation (DBS) which is already used in the clinic to treat patients with Parkinson’s disease. It turned out that during DBS the mice were free of any symptoms but when after DBS the symptoms returned.

All in all it was an interesting talk by Roy Sillitoe but it was quite difficult to follow due to the speed with which he went through everything and because of the many medical terms that I am not familiar with. In the end however the basics were clear to me and the model they developed seems very promising.



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